tbuckley/cabot-search huggingface dataset:
Combination Nivolumab, CD137 Agonism, and Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes for Patients with Metastatic Melanoma
Authors: MacLean S. Hall, John E. Mullinax, Cheryl A. Cox, Amy M. Hall, Matthew S. Beatty, Jamie Blauvelt, Patrick Innamarato, Luz Nagle, Holly Branthoover, Doris Wiener, Benjamin Schachner, Alberto J. Martinez, Allison D. Richards, Carolyn J. Rich, Marjorie Colón Colón, Michael J. Schell, Jamie K. Teer, Nikhil I. Khushalani, Jeffrey S. Weber, James J. Mulé, Vernon K. Sondak, Shari Pilon-Thomas, Amod A. Sarnaik
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Metastatic melanoma is a tumor amenable to immunotherapy in part due to the presence of antigen-specific tumor-infiltrating lymphocytes (TIL). These T cells can be activated and expanded for adoptive cell transfer (ACT), which has resulted in relatively high rates of clinical responses. Similarly, immune checkpoint inhibitors, specifically programmed cell death protein 1 (PD-1) blocking antibodies, augment antitumor immunity and increase the influx of T cells into tumors. Thus, we hypothesized that addition of PD-1 inhibition may improve the outcomes for patients undergoing ACT with TILs. Patients and Methods: Patients with stage III/IV metastatic melanoma with unresectable disease who were anti–PD-1 treatment-naïve were enrolled. TILs were generated in the presence of anti–4-1BB antibody in vitro and expanded for ACT. Patients in cohort 1 received TIL infusion followed by nivolumab. Patients in cohort 2 also received nivolumab prior to surgical harvest and during TIL production. Results: A total of 11 patients were enrolled, all of whom were evaluated for response, and nine completed ACT. Predominantly CD8+ TILs were successfully expanded from all ACT-treated patients and were tumor reactive in vitro. The trial met its safety endpoint, as there were no protocol-defined dose-limiting toxicity events. The objective response rate was 36%, and median progression-free survival was 5 months. Two nonresponders who developed new metastatic lesions were analyzed to determine potential mechanisms of therapeutic resistance, which included clonal divergence and intrinsic TIL dysfunction. Conclusions: Combination therapy with TILs and nivolumab was safe and feasible for patients with metastatic melanoma and provides important insights for future therapeutic developments in ACT with TILs.
Fast and scalable search of whole-slide images via self-supervised deep learning
Authors: Chengkuan Chen, Ming Y. Lu, Drew F. K. Williamson, Tiffany Y. Chen, Andrew J. Schaumberg, Faisal Mahmood
Journal: Nature Biomedical Engineering (2022)

Abstract The adoption of digital pathology has enabled the curation of large repositories of gigapixel whole-slide images (WSIs). Computationally identifying WSIs with similar morphologic features within large repositories without requiring supervised training can have significant applications. However, the retrieval speeds of algorithms for searching similar WSIs often scale with the repository size, which limits their clinical and research potential. Here we show that self-supervised deep learning can be leveraged to search for and retrieve WSIs at speeds that are independent of repository size. The algorithm, which we named SISH (for self-supervised image search for histology) and provide as an open-source package, requires only slide-level annotations for training, encodes WSIs into meaningful discrete latent representations and leverages a tree data structure for fast searching followed by an uncertainty-based ranking algorithm for WSI retrieval. We evaluated SISH on multiple tasks (including retrieval tasks based on tissue-patch queries) and on datasets spanning over 22,000 patient cases and 56 disease subtypes. SISH can also be used to aid the diagnosis of rare cancer types for which the number of available WSIs is often insufficient to train supervised deep-learning models.
Hopeful not helpless: How doctors are combating climate change
Authors: Elisabeth Mahase
Journal: BMJ (2022)

Health systems in sub-Saharan Africa have remained overstretched from dealing with endemic diseases, which limit their capacity to absorb additional stress from new and emerging infectious diseases. Against this backdrop, the rapidly evolving COVID-19 pandemic presented an additional challenge of insufficient hospital beds and human resource for health needed to deliver hospital-based COVID-19 care. Emerging evidence from high-income countries suggests that a ‘virtual ward’ (VW) system can provide adequate home-based care for selected patients with COVID-19, thereby reducing the need for admissions and mitigate additional stress on hospital beds. We established a VW at the Medical Research Council Unit, The Gambia at the London School of Hygiene and Tropical Medicine, a biomedical research institution located in The Gambia, a low-income west African country, to care for members of staff and their families infected with COVID-19. In this practice paper, we share our experience focusing on the key components of the system, how it was set up and successfully operated to support patients with COVID-19 in non-hospital settings. We describe the composition of the multidisciplinary team operating the VW, how we developed clinical standard operating procedures, how clinical oversight is provided and the use of teleconsultation and data capture systems to successfully drive the process. We demonstrate that using a VW to provide an additional level of support for patients with COVID-19 at home is feasible in a low-income country in sub-Saharan Africa. We believe that other low-income or resource-constrained settings can adopt and contextualise the processes described in this practice paper to provide additional support for patients with COVID-19 in non-hospital settings.
Integrative analyses for the identification of idiopathic pulmonary fibrosis-associated genes and shared loci with other diseases
Authors: Ming Chen, Yiliang Zhang, Taylor Adams, Dingjue Ji, Wei Jiang, Louise V Wain, Michael Cho, Naftali Kaminski, Hongyu Zhao
Journal: Thorax (2022)

Although genome-wide association studies (GWAS) have identified many genomic regions associated with idiopathic pulmonary fibrosis (IPF), the causal genes and functions remain largely unknown. Many single-cell expression data have become available for IPF, and there is increasing evidence suggesting a shared genetic basis between IPF and other diseases.
Myocardial Extracellular Volume Expansion in Type 2 Diabetes Is Associated With Ischemic Heart Disease, Autonomic Neuropathy, and Active Smoking
Authors: Annemie Stege Bojer, Martin Heyn Sørensen, Peter Gæde, Per Lav Madsen
Journal: Diabetes Care (2022)

OBJECTIVE Myocardial interstitial fibrosis expands the extracellular volume (ECV) and in patients with type 2 diabetes is implicated in development of heart failure. ECV can be determined with gadolinium contrast MRI. We investigated which known risk factors for cardiovascular disease were associated with increased ECV in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 296 patients with type 2 diabetes and 25 sex and age-matched control subjects were included in a cross-sectional MRI study. The influence of risk factors on ECV was investigated with multiple regression analysis. RESULTS Control subjects and patients with type 2 diabetes without complications had similar ECV (mean ± SD 27.4 ± 2.1% vs. 27.9 ± 2.6%, P = 0.4). Compared with patients without, ECV was significantly increased in patients with one or more complications (29.0 ± 3.3%, P = 0.02). Both in univariable analysis and after multivariable adjustment, ischemic heart disease, autonomic neuropathy, and active smoking were associated with increased levels of ECV. Active smoking exhibited the largest effect size (β = 2.0 percentage points, 95% CI 0.7–3.3). Former smokers ECV similar to that of never smokers. Albuminuria and systolic blood pressure were inversely associated with ECV in multivariable analysis, but after adjustment for medication suspected to affect ECV, the association with albuminuria was no longer significant (P = 0.1). Sodium–glucose cotransporter 2 inhibitor treatment was not significantly associated with reduced ECV (−0.8%, 95% CI −1.7 to 0.06, P = 0.067). CONCLUSIONS Patients with complications of diabetes have increased ECV, not seen in patients without complications. Ischemic heart disease, autonomic neuropathy, and active but not former smoking were highly associated with increased ECV.
Intensive Blood Pressure Lowering in Patients With Malignant Left Ventricular Hypertrophy
Authors: Simon B. Ascher, James A. de Lemos, MinJae Lee, Elaine Wu, Elsayed Z. Soliman, Ian J. Neeland, Dalane W. Kitzman, Christie M. Ballantyne, Vijay Nambi, Anthony A. Killeen, Joachim H. Ix, Michael G. Shlipak, Jarett D. Berry
Journal: Journal of the American College of Cardiology (2022)
The response of subgroups of patients with schizophrenia to different antipsychotic drugs: a systematic review and meta-analysis
Authors: Stefan Leucht, Anna Chaimani, Marc Krause, Johannes Schneider-Thoma, Dongfang Wang, Shimeng Dong, Myrto Samara, Natalie Peter, Maximilian Huhn, Josef Priller, John M Davis
Journal: The Lancet Psychiatry (2022)
Colchicine and aspirin in community patients with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial
Authors: John W Eikelboom, Sanjit S Jolly, Emilie P Belley-Cote, Richard P Whitlock, Sumathy Rangarajan, Lizhen Xu, Laura Heenan, Shrikant I Bangdiwala, Wadea M Tarhuni, Mohamed Hassany, Anna Kontsevaya, William Harper, Sanjib Kumar Sharma, Patricio Lopez-Jaramillo, Antonio L Dans, Lia M Palileo-Villanueva, Alvaro Avezum, Prem Pais, Denis Xavier, Camilo Felix, Afzalhussein Yusufali, Renato D Lopes, Otavio Berwanger, Zeeshan Ali, Sean Wasserman, Sonia S Anand, Jackie Bosch, Shurjeel Choudhri, Michael E Farkouh, Mark Loeb, Salim Yusuf
Journal: The Lancet Respiratory Medicine (2022)
The promise of a model-based psychiatry: building computational models of mental ill health
Authors: Tobias U Hauser, Vasilisa Skvortsova, Munmun De Choudhury, Nikolaos Koutsouleris
Journal: The Lancet Digital Health (2022)

<h2>Summary</h2> Computational models have great potential to revolutionise psychiatry research and clinical practice. These models are now used across multiple subfields, including computational psychiatry and precision psychiatry. Their goals vary from understanding mechanisms underlying disorders to deriving reliable classification and personalised predictions. Rapid growth of new tools and data sources (eg, digital data, gamification, and social media) requires an understanding of the constraints and advantages of different modelling approaches in psychiatry. In this Series paper, we take a critical look at the range of computational models that are used in psychiatry and evaluate their advantages and disadvantages for different purposes and data sources. We describe mechanism-driven and mechanism-agnostic computational models and discuss how interpretability of models is crucial for clinical translation. Based on these evaluations, we provide recommendations on how to build computational models that are clinically useful.
Colchicine and the combination of rivaroxaban and aspirin in patients hospitalised with COVID-19 (ACT): an open-label, factorial, randomised, controlled trial
Authors: John W Eikelboom, Sanjit S Jolly, Emilie P Belley-Cote, Richard P Whitlock, Sumathy Rangarajan, Lizhen Xu, Laura Heenan, Shrikant I Bangdiwala, Maria Luz Diaz, Rafael Diaz, Afzalhussein Yusufali, Sanjib Kumar Sharma, Wadea M Tarhuni, Mohamed Hassany, Alvaro Avezum, William Harper, Sean Wasserman, Aysha Almas, Oxana Drapkina, Camilo Felix, Renato D Lopes, Otavio Berwanger, Patricio Lopez-Jaramillo, Sonia S Anand, Jackie Bosch, Shurjeel Choudhri, Michael E Farkouh, Mark Loeb, Salim Yusuf
Journal: The Lancet Respiratory Medicine (2022)
From promise to practice: towards the realisation of AI-informed mental health care
Authors: Nikolaos Koutsouleris, Tobias U Hauser, Vasilisa Skvortsova, Munmun De Choudhury
Journal: The Lancet Digital Health (2022)

In this Series paper, we explore the promises and challenges of artificial intelligence (AI)-based precision medicine tools in mental health care from clinical, ethical, and regulatory perspectives. The real-world implementation of these tools is increasingly considered the prime solution for key issues in mental health, such as delayed, inaccurate, and inefficient care delivery. Similarly, machine-learning-based empirical strategies are becoming commonplace in psychiatric research because of their potential to adequately deconstruct the biopsychosocial complexity of mental health disorders, and hence to improve nosology of prognostic and preventive paradigms. However, the implementation steps needed to translate these promises into practice are currently hampered by multiple interacting challenges. These obstructions range from the current technology-distant state of clinical practice, over the lack of valid real-world databases required to feed data-intensive AI algorithms, to model development and validation considerations being disconnected from the core principles of clinical utility and ethical acceptability. In this Series paper, we provide recommendations on how these challenges could be addressed from an interdisciplinary perspective to pave the way towards a framework for mental health care, leveraging the combined strengths of human intelligence and AI.
UCART19, a first-in-class allogeneic anti-CD19 chimeric antigen receptor T-cell therapy for adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (CALM): a phase 1, dose-escalation trial
Authors: Reuben Benjamin, Nitin Jain, Marcela V Maus, Nicolas Boissel, Charlotte Graham, Agnieszka Jozwik, Deborah Yallop, Marina Konopleva, Matthew J Frigault, Takanori Teshima, Koji Kato, Floriane Boucaud, Svetlana Balandraud, Athos Gianella-Borradori, Florence Binlich, Ibtissam Marchiq, Sandra Dupouy, Maria Almena-Carrasco, Matthieu Pannaux, Sylvain Fouliard, Eolia Brissot, Mohamad Mohty, Reuben Benjamin, Charlotte Graham, Agnieszka Jozwik, Deborah Yallop, Laarni Bonganay, Lorraine Catt, Jackie Chappell, Gary Cheung, Vicky Chu, Kirsty Cuthill, Steven Devereux, Alan Dunlop, Rose Ellard, Farzin Farzeneh, Najeem Folarin, Elka Giemza, Shireen Kassam, Majid Kazmi, Andrea Kuhnl, Jen Lewis, Maria Liskova, Alice Mason, Victoria Metaxa, Ghulam Mufti, Helena Munro, Antonio Pagliuca, Piers Patten, Victoria Potter, Carmel Rice, Adeel Saleem, Robin Sanderson, Orla Stewart, Elias Jabbour, Nitin Jain, Emily Jones, Hagop Kantarjian, Partow Kebriaei, Marina Konopleva, Kara McGee, William Wierda, Jami Brown, Keagan Casey, Matthew Frigault, Hanno Hock, Richard Mathews, Marcela Maus, Meaghan A McKeown, Thomas Spitzer, Vesselina Toncheva, Elie Azoulay, Nicolas Boissel, Sophie Caillat-Zucman, Karine Celli-Lebras, Emmanuelle Clappier, Raphael Itzykson, Jérôme Larghero, Etienne Lengliné, Isabelle Madelaine, Martine Meunier, Florence Rabian, Emmanuel Raffoux, Marie-Thérèse Tremorin, Agnes Bonnin, Eolia Brissot, Anne Daguenel-Nguyen, Remy Dulery, Tounes Ledraa, Florent Malard, Clemence Mediavilla, Mohamad Mohty, Anne Vekhoff, Takanori Teshima, Koji Kato
Journal: The Lancet Haematology (2022)
Prognostic factors associated with mortality among patients receiving venovenous extracorporeal membrane oxygenation for COVID-19: a systematic review and meta-analysis
Authors: Alexandre Tran, Shannon M Fernando, Bram Rochwerg, Ryan P Barbaro, Carol L Hodgson, Laveena Munshi, Graeme MacLaren, Kollengode Ramanathan, Catherine L Hough, Laurent J Brochard, Kathryn M Rowan, Niall D Ferguson, Alain Combes, Arthur S Slutsky, Eddy Fan, Daniel Brodie
Journal: The Lancet Respiratory Medicine (2022)
Mental health in the digital age
Authors: None The Lancet Digital Health
Journal: The Lancet Digital Health (2022)

October 10 is World Mental Health Day. The theme to "Make mental health and well-being for all a global priority" highlights the ubiquitous need to address the world's growing mental health crisis. Although effective interventions for mental disorders exist, barriers to access mean there has been no evidence of a global reduction in mental health burden since 1990. In fact, a 2022 world mental health report published by WHO showed that global prevalence of anxiety and depressive disorders rose more than 25% during the first year of the COVID-19 pandemic.
Single-dose carboplatin followed by involved-node radiotherapy for stage IIA and stage IIB seminoma (SAKK 01/10): a single-arm, multicentre, phase 2 trial
Authors: Alexandros Papachristofilou, Jens Bedke, Stefanie Hayoz, Ulrich Schratzenstaller, Miklos Pless, Marcus Hentrich, Susanne Krege, Anja Lorch, Daniel-M Aebersold, Paul Martin Putora, Dominik-R Berthold, Deborah Zihler, Friedemann Zengerling, Annette Dieing, Arndt-Christian Mueller, Corinne Schaer, Christine Biaggi, Silke Gillessen, Richard Cathomas
Journal: The Lancet Oncology (2022)
Rheumatoid arthritis, psoriatic arthritis, and axial spondyloarthritis epidemiology in England from 2004 to 2020: An observational study using primary care electronic health record data
Authors: Ian C. Scott, Rebecca Whittle, James Bailey, Helen Twohig, Samantha L. Hider, Christian D Mallen, Sara Muller, Kelvin P. Jordan
Journal: The Lancet Regional Health - Europe (2022)
Spatial transcriptomic analysis delineates epithelial and mesenchymal subpopulations and transition stages in childhood ependymoma
Authors: Rui Fu, Gregory A Norris, Nicholas Willard, Andrea M Griesinger, Kent A Riemondy, Vladimir Amani, Enrique Grimaldo, Faith Harris, Todd C Hankinson, Siddhartha Mitra, Timothy A Ritzmann, Richard R Grundy, Nicholas K Foreman, Andrew M Donson
Journal: Neuro-Oncology (2022)

The diverse cellular constituents of childhood brain tumor ependymoma, recently revealed by single cell RNA-sequencing, may underly therapeutic resistance. Here we use spatial transcriptomics to further advance our understanding of the tumor microenvironment, mapping cellular subpopulations to the tumor architecture of ependymoma posterior fossa subgroup A (PFA), the commonest and most deadly childhood ependymoma variant.Spatial transcriptomics data from intact PFA sections was deconvoluted to resolve the histological arrangement of neoplastic and non-neoplastic cell types. Key findings were validated using immunohistochemistry, in vitro functional assays and outcome analysis in clinically-annotated PFA bulk transcriptomic data.PFA are comprised of epithelial and mesenchymal histological zones containing a diversity of cellular states, each zone including co-existing and spatially distinct undifferentiated progenitor-like cells; a quiescent mesenchymal zone population, and a second highly mitotic progenitor population that is restricted to hypercellular epithelial zones and that is more abundant in progressive tumors. We show that myeloid cell interaction is the leading cause of mesenchymal transition in PFA, occurring in zones spatially distinct from hypoxia-induced mesenchymal transition, and these distinct EMT-initiating processes were replicated using in vitro models of PFA.These insights demonstrate the utility of spatial transcriptomics to advance our understanding of ependymoma biology, revealing a clearer picture of the cellular constituents of PFA, their interactions and influence on tumor progression.
Prediction of response to lomustine-based chemotherapy in glioma patients at recurrence using MRI and FET PET
Authors: Michael M Wollring, Jan-Michael Werner, Elena K Bauer, Caroline Tscherpel, Garry S Ceccon, Philipp Lohmann, Gabriele Stoffels, Christoph Kabbasch, Roland Goldbrunner, Gereon R Fink, Karl-Josef Langen, Norbert Galldiks
Journal: Neuro-Oncology (2022)

We evaluated O-(2-[18F]fluoroethyl)-l-tyrosine (FET) PET and MRI for early response assessment in recurrent glioma patients treated with lomustine-based chemotherapy.Thirty-six adult patients with WHO CNS grade 3 or 4 gliomas (glioblastoma, 69%) at recurrence (median number of recurrences, 1; range, 1-3) were retrospectively identified. Besides MRI, serial FET PET scans were performed at baseline and early after chemotherapy initiation (not later than two cycles). Tumor-to-brain ratios (TBR), metabolic tumor volumes (MTV), the occurrence of new distant hotspots with a mean TBR >1.6 at follow-up, and the dynamic parameter time-to-peak were derived from all FET PET scans. PET parameter thresholds were defined using ROC analyses to predict PFS of ≥6 months and OS of ≥12 months. MRI response assessment was based on RANO criteria. The predictive values of FET PET parameters and RANO criteria were subsequently evaluated using univariate and multivariate survival estimates.After treatment initiation, the median follow-up time was 11 months (range, 3-71 months). Relative changes of TBR, MTV, and RANO criteria predicted a significantly longer PFS (all P ≤ .002) and OS (all P ≤ .045). At follow-up, the occurrence of new distant hotspots (n ≥ 1) predicted a worse outcome, with significantly shorter PFS (P = .005) and OS (P < .001). Time-to-peak changes did not predict a significantly longer survival. Multivariate survival analyses revealed that new distant hotspots at follow-up FET PET were most potent in predicting non-response (P < .001; HR, 8.578).Data suggest that FET PET provides complementary information to RANO criteria for response evaluation of lomustine-based chemotherapy early after treatment initiation.
Homeobox A3 and KDM6A cooperate in transcriptional control of aerobic glycolysis and glioblastoma progression
Authors: Rui Yang, Guanghui Zhang, Zhen Dong, Shanshan Wang, Yanping Li, Fuming Lian, Xiaoran Liu, Haibin Li, Xiaonan Wei, Hongjuan Cui
Journal: Neuro-Oncology (2022)

Alterations in transcriptional regulators of glycolytic metabolism have been implicated in brain tumor growth, but the underlying molecular mechanisms remain poorly understood.Knockdown and overexpression cells were used to explore the functional roles of HOXA3 in cell proliferation, tumor formation, and aerobic glycolysis. Chromatin immunoprecipitation, luciferase assays, and western blotting were performed to verify the regulation of HK2 and PKM2 by HOXA3. PLA, Immunoprecipitation, and GST-pull-down assays were used to examine the interaction of HOXA3 and KDM6A.We report that transcription factor homeobox A3 (HOXA3), which is aberrantly highly expressed in glioblastoma (GBM) patients and predicts poor prognosis, transcriptionally activates aerobic glycolysis, leading to a significant acceleration in cell proliferation and tumor growth. Mechanically, we identified KDM6A, a lysine-specific demethylase, as an important cooperator of HOXA3 in regulating aerobic glycolysis. HOXA3 activates KDM6A transcription and recruits KDM6A to genomic binding sites of glycolytic genes, targeting glycolytic genes for transcriptional activation by removing the suppressive histone modification H3K27 trimethylation. Further evidence demonstrates that HOXA3 requires KDM6A for transcriptional activation of aerobic glycolysis and brain tumor growth.Our findings provide a novel molecular mechanism linking HOXA3-mediated transactivation and KDM6A-coupled H3K27 demethylation in regulating glucose metabolism and GBM progression.